Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
DOI: 10.13294/j.aps.2017.0062 http://www.actaps.com.cn 541
Influence of insulin on growth hormone secretion, level and growth
QIU Han1, YANG Jin-Kui2, CHEN Chen3, *
1Department of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; 2Endocrinology
Department, Tongren Hospital, Capital Medical University, Beijing 100730, China; 3School of Biomedical Science, University of
Queensland, Brisbane, Qld 4072, Australia
Abstract: Growth hormone (GH), as a vital hormone, has to experience a series of processes to fulll its function including secretion,
entering the circulation to reach target tissues (pre-receptor process), binding on the GH receptor (GHR) and triggering signaling
inside cells (post-GHR process). Insulin can directly or indirectly inuence part of these processes. GH secretion from pituitary
somatotropes is regulated by GH-releasing hormone (GHRH) and somatostatin (SS) from hypothalamus. Insulin may exert positive or
negative effects on the neurons expressing GHRH and SS and somatotropes under healthy and pathological conditions including
obesity and diabetes. Glucose and lipid levels in circulation and dietary habits may inuence the effect of insulin on GH secretion.
Insulin may also affect GHR sensitivity and the level of insulin-like growth factor 1 (IGF-1), thus inuence the level of GH. The GH
signaling is also important for GH to play its role. GH signaling involves GHR/JAK2/STATs, GHR/JAK2/SHC/MAPK and GH/
insulin receptor substrate (IRS)/PI3K/Akt pathways. These pathways may be shared by insulin, which is the basis for the interaction
between insulin and GH, and insulin may attenuate or facilitate the GH signal by inuencing molecules in the pathways. Many factors
are related to the effect of insulin, among them the most important ones are duration of action and amount of insulin. The tendency
of insulin-reduced GH signaling becomes obvious with increased dose and acting time of insulin. The participation of suppressor
of cytokine signaling (SOCS), the interaction between JAK2 and IRS, and GHR sensitivity should also be considered when discovering
GH signal. The involvement of SS in response to insulin is not clear yet. The details of how GH secretion, level and signaling change
in response to time and dose of insulin treatment warrant further studies.
Key words: insulin; growth hormone; somatostatin; obesity; diabetes; signal pathway
邱 涵1，杨金奎2，陈 晨3,*
1中山大学中山医学院法医学系，广州 510080；2首都医科大学同仁医院内分泌科，北京 100730；3昆士兰大学生物医学科学
摘 要：生长激素(growth hormone, GH)在行使其功能时需要经历一系列的过程，包括从垂体分泌和进入血液循环到达靶器官
或细胞(受体前过程)以及和生长激素受体(GH receptor, GHR)结合并引发细胞内信号转导(受体后过程)。胰岛素可以直接或间
mone, GHRH)和生长激素抑制素(somatostatin, SS)，在生理或病理条件下，胰岛素可以对这两种激素以及GH分泌细胞施加不
GHR的敏感性，以及影响胰岛素样生长因子-1 (insulin-like growth factor 1, IGF-1)，进而影响GH。受体后过程也是GH行使功
Received 2017-02-20 Accepted 2017-06-10
Research from the corresponding author’s laboratory was partially supported by NHMRC-NSFC and University of Queensland, Australia.
*Corresponding author. Tel: +61-7-33653856; Fax: +61-7-33652398; E-mail: firstname.lastname@example.org
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
Growth hormone (GH) plays an important role in physical
growth and development by maintaining the normal
structure and functionality of the body through cell
regeneration and protein synthesis [1, 2]. Insulin is a vital
hormone playing a number of roles in the body metab-
olism, especially in the regulation of blood glucose
levels by signaling the liver, muscle and adipose cells
to take in glucose from the blood circulation. As very
important metabolic regulatory hormones, both GH and
insulin work in concert to implement their effects on
the cellular metabolism and biogenic activities. Their
interaction and balance are critical under both patho-
logical and physiological conditions. Understanding the
interaction between GH and insulin is the prerequisite
of understanding the mechanism of many endocrine
processes in maintaining normal metabolic balance, as
well as in metabolic disorders. The effect of GH on in-
sulin, especially on insulin’s sensitivity, has been inten-
sively investigated in past few decades since 1930s .
However, given the increasing use of insulin in hor-
mone-replacement therapies to treat diabetes, it is of
great importance and interest to clarify the inuence of
insulin on GH, which is in the process of exploration.
About 50 years ago, Hazelwood and his colleagues
found that diabetes could exert an impact on GH con-
tent inside pituitary gland . In 1978, it was shown that
insulin receptors (IR) were widely distributed in the
central nervous system . Then in 1992, Menon et al.
found that GH-binding protein decreased in children
with type 1 diabetes (T1D) . In 1999, it has been
demonstrated that insulin may inhibit GH signaling .
All these studies have indicated complicated actions of
insulin on GH, even though the mechanisms are not
totally understood. To better discuss insulin’s action on
GH, we divide the roles played by GH into two parts:
the pre-receptor process including GH secretion and the
maintenance of GH levels, and the post-GH receptor
(GHR) process which mainly refers to GH signaling.
GH secretion is regulated in a hypothalamus-con-
trolled pattern, which involves the stimulation or inhi-
bition on somatotropes by GH-releasing hormone
(GHRH) or somatostatin (SS) respectively. GH secre-
tion is also inuenced by insulin-like growth factor 1
(IGF-1), which involves negative feedback mechanism.
GH level is greatly determined by GH secretion, but it
is also influenced by insulin to a great extent in both
physiological and pathological conditions. The prole
of plasma GH is related to GH’s functions. The GH
level in circulation changes with a number of factors.
The matters affected by insulin, including GHRH, SS,
IGF-1, the blood glucose and lipid concentration, can
directly or indirectly inuence GH [8–12]. GH signaling
is indispensable for GH to play its part. GH binds with
the GHR, setting up the post-GHR process. The most
essential signal pathways mediated by GHR include
signal transducer and activator of transcription (STAT)
pathway, mitogen-activated protein kinase (MAPK)
pathway and phosphoinositide 3-kinase (PI3K)/Akt
pathway . Previous studies have implied that insulin
may affect GH hormone and downstream signals in a
time- and dose-dependent manner both in vivo and in
vitro, even though there are conicting results under
different experimental conditions [12–15].
1 GH secretion, GH level and GH signalling:
Functioning process of GH
GH, a single-chain polypeptide containing 191 amino
acids, also known as somatotropin, is a hormone that
motivates physical growth and organism development
in human and animals. It also plays an important role in
sustaining the normal structure of the whole body.
Besides the well-known function to facilitate long term
postnatal growth, GH has a vital metabolic regulatory
effect alone or with other hormones on reproduction
and aging (cell reproduction and regeneration), as well
as metabolic processes [2, 16–18].
To function inside the body, GH has to be synthe-
sized, stored, and secreted by somatotropic cells (located
in anterior pituitary gland) by receiving the stimulation
of GHRH from hypothalamus. Then GH goes into the
blood circulation and to distant organs including liver,
QIU Han et al.: Inuence of Insulin on GH Secretion, Level and Signaling 543
muscles and adipose tissues, to act on all cells possess-
ing GHR . These processes are pre-GHR processes
which involve two fundamental elements: the secretion
of GH and the maintenance of GH level in blood circu-
lation. During these processes, GH can affect and interact
with other hormones, i.e., taking action on pancreatic
islets to regulate insulin and glucagon. Also, it can be
inuenced by other hormones or matters. After GH is
recognized by GHR, it can bind to the receptor, go into
the cell and pass down its signal to motivate a variety
of cellular activities through different signal pathways.
The integrity of GH signal pathways is indispensable
for the transmission of GH signal and implementation
of its function in cell level. This process is the post-
1.1 The secretion of GH
GH secretion is completed and regulated in an axial
pattern. Hypothalamus perceives physiological stimulus
and regulates rhythm of life and releases GHRH, which
is an endogenous hormone. It is also a peptide hormone,
containing 43–44 amino acids. GHRH binds to the
GHRH-receptor of somatotropes in the anterior pituitary
gland. Then, the stored GH inside somatotropes can be
released into circulation and ow through various organs
and cells to implement its function, including going
back to the hypothalamus and pituitary to give feedback.
GHRH is released in a pulsatile way, which leads to the
pulsatile secretion of GH. There is another hormone
existing in the hypothalamus called somatotropin-
releasing inhibitory factor (SRIF, also known as SS or
SST), which is also known as GH- inhibiting hormone
(GHIH) that exists in the digestive organs too, partici-
pating in the secretion of GH. SS is also a peptide
hormone, and it has six different constitutions from
six different genes in zebrash, but humans only pos-
sess one: SS. SS can inhibit GH secretion by inhibiting
the release of GH from somatotropes, thus opposing
the effects of GHRH. SS also has many kinds of recep-
tors exerting different functions besides regulating GH
secretion, such as inhibiting the glucagon to control
glucose in blood . As regulators of GH secretion,
GHRH is more systemic than SS. SS usually plays an
assistant role and works together with other hormones.
GHRH and SS regulate GH secretion together to keep
the normal concentration of GH in circulation [9, 21, 22].
Some hormones or drugs can exert influence on GH
secretion by exerting action on GHRH, SS, and somato-
tropes. Apart from GHRH and SS, GH secretagogue
(GHS) ghrelin also facilitates the secretion of GH. The
axial regulation pattern involves negative feedback
mechanism: GHR exists on pituitary GH cells and
hypothalamus GHRH/SS neurons to receive feedback
and regulate GH release. GH/GHR/IGF-1 axis is another
important axis for regulation of GH secretion which
involves negative feedback mechanism. IGF-1 is
considered GH secretion inhibitor. When IGF-1 gene
was deleted from liver, the level of GHS receptor in
pituitary went up, leading to an improved GH secre-
tion . The GH/IGF-1 system plays a role in the inter-
action among adipose tissue, liver, and pituitary .
1.2 GH level in circulation
GH level in blood circulation is essential for normal
metabolism. When the frequency and quantity of GH
pulsatile secretion are influenced, GH concentration
fluctuates. GHR sensitivity also has an effect on GH
level because normal GHR sensitivity is important to
the successful GH utilization. When GHR sensitivity is
impaired, body enhances GH level to make up. GH
prole gives feedback to hypothalamus, the upper head
of axis, thus maintaining a normal concentration. GH/
IGF-1 axis also plays a part in regulating GH level. An
experiment showed that liver-specic deletion of IGF-I
in mice (LI-IGF-I−/−) gave rise to declined circulating
IGF-I and increased plasma GH levels .
The prole of plasma GH is correlated to physiologi-
cal and pathological conditions. GH not only acceler-
ates lipolysis, but also regulates glucose metabolism,
and has the ability to enhance blood glucose concentra-
tion. Therefore, diet habits and metabolic diseases can
inuence GH level by changing blood glucose and lipid
content. Non-esterified fatty acid (NEFA) has been
considered a factor to influence GH level, for excess
NEFA restrains GH level . But NEFA and GH level
are not always in inverse proportion to each other. The
regulation of GH level may involve the participation of
insulin. It was found that the GH offsets the effect of
insulin on glucose homoeostasis, so glucose metabo-
lism also accounts for regulating GH level [26, 27]. T1D
patients were found to have a lower insulin level and
higher GH level . This implies that the maintenance
of GH level can be disturbed by other hormones, espe-
cially insulin, which possesses reverse metabolic func-
tions to GH. For the regulation pattern of GH secretion
and GH level, see Fig. 1.
1.3 The signaling of GH
Signalling inside the cell is a post-GHR process, which
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
is the cornerstone for the cellular activities. It is the last
step for GH to function. GH exerts its actions through a
series of signalling pathways and stimulates the phos-
phorylation of groups of molecules. The beginning of
GH signal transmission is the combination of GH to
two GHR molecules. GHR is a member of superfamily
of cytokine/hematopoietic receptors. However, GHR
lacks inherent activity of tyrosine kinase. Fundamentally,
it is connected with a tyrosine-kinase called Janus
kinase (JAK) 2 [29, 30]. After GHR is bound, the
di merization action results in the auto-phosphorylation
of one or more certain tyrosine(s) of JAK2, which
brings a conformational alternation in JAK2 that
changes (decreases or stimulates) JAK2 activity. For
instance, phosphorylation of tyrosine 1 007 has been
considered to expose the ATP or downstream binding
sites, which can also be combined with the negative
regulators of cytokine -- suppressor of cytokine signal-
ing (SOCS), and then stimulates the GHR on tyrosine
residues inside cells [31–33]. Phosphorylated residues on
GHR and JAK2 are docked with a variety of intracellular
transmission intermediators including the STAT family
STAT-1, 3, 5 (including 5a and 5b), and other intracel-
lular substrates including insulin receptor substrate 1
(IRS-1), IRS-2 and src homology and collagen (SHC)
protein . Replenishment of these proteins to the
GHR-JAK2 complexes permits GH to execute a variety
of physiological function . The removal of tyrosine
phosphatises in GHR-JAK2 complex draws the signal
of GH to the end [30, 35]. Among various kinds of cellular
activities, transcription of genes is the most important
one. Three major signal pathways are of great signicance
in this post-GHR process: GHR/JAK2/STATs, GHR/
JAK2/SHC/MAPK and GH/IRS/PI3K/Akt pathways .
STAT family contains many subtypes, and the close
relationship between GHR and STAT5b has been
Fig. 1. The physical regulation pattern of GH proles. GH secretion is completed and regulated in an axial pattern. GH is synthesized,
stored, and secreted by somatotropic cells (located in anterior pituitary gland) by receiving the stimulation of GHRH from hypothala-
mus. Meanwhile, GH in pituitary is regulated by somatostatin existing in the hypothalamus, which can be stimulated by insulin from
pancreatic islets and inhibit GH secretion. Insulin can also bind to the insulin receptor (IR) on somatotropes in pituitary and inhibit
GH secretion. An excessive high level of GH in circulation gives negative feedback to hypothalamus and pituitary gland, preventing
GH secretion. GH/GHR/IGF-1 axis is another important axis for regulation of GH secretion, which participates in controlling GH lev-
el in circulation. GH goes to distance organs including liver, muscles, bones and adipose tissues and begins to take action on all cells
possessing GHR. Abbreviations: −, inhibition; +, stimulation; GH, growth hormone; GHR, growth hormone receptor; GHRH, growth
hormone releasing hormone; IGF-1, insulin-like growth factor-1.
QIU Han et al.: Inuence of Insulin on GH Secretion, Level and Signaling 545
discovered, although STAT5a also plays a role in GH
signal [36–38]. STAT5b is sensitive to pulsatile secretion
of GH . GH-induced tyrosine phosphorylation of
STAT5B is followed by the relocation of cytoplasmic
STAT5 proteins complex to the nuclear area and medi-
ated by an SH2 domain-phosphorylated tyrosine action.
Then target genes’ transcription is motivated, mainly
including c-fos, serine protease inhibitor (spi 2.1), and
SOCS, which are related to somatic growth and devel-
opment and metabolic functions of GH [30, 40–42]. The
growth effect of GH on muscle relies on STAT5b:
muscle IGF-1 transcript and muscle mass weaken due
to the muscle-specic deletion of STAT5B . In
humans, clinical research showed that growth failure
and disorders were related to STAT5b mutation, implying
an irreplaceable post of STAT5b in GH signalling [44–46].
SOCSs are in the downstream pathway of STAT5, and
GH induces four molecules in them, including SOCS-
1, 2, 3 and CIS. The SOCSs family is involved in atten-
uating the GH-induced stimulation of JAK2. Each of
them can block the auto-phosphorylation of JAK2 by
competing for the binding sites in GHR with STATs [47–49].
The Ras-MAPK pathway is also crucial in GH
signalling. In most cases, GH activates GHR/JAK2/
SHC/MAPK pathway by JAK2 phosphorylation of the
protein SHC [50, 51]. Noticeably, IRS-1 is shown to be
involved in this pathway and plays a positive role by
facilitating GH-induced cell regeneration mediated by
MAPK . GH can also induce the phosphorylation of
IRS . GH appears to facilitate tyrosine phosphorylation
of IRSs and build up their association with PI3K in a
variety of GH-responsive cells to full its function in
lipid and glucose metabolism [54–58]. Activation of the
GH/IRS/PI3K/Akt pathway is mediated by JAK2, and
there is no overt direct connection between the IRS
proteins and with the GHR .
Additionally, signal molecules in GH signalling
process like STAT, PI3K and MAPK do not serve for
GH merely; instead they are shared by many other
hormones. This is the basis for the interaction in the
cellular level between GH and other hormones especially
2 The effect of insulin on the pre-receptor
process: the effect on GH secretion and GH
level by insulin
In early stage of research, it is noticed that there is a
mutual effect of GH and insulin on each other secretion
inside mammalian bodies, including human beings.
Considering the inverse physiological function of these
two hormones, which mainly refers to the function of
regulating the lipogenesis and lipolysis, and the effect
on glucose metabolism, one may easily speculate the
inverse relationship between insulin and GH. With the
increasing incidence of diabetes, scholars have paid
more attention to the effect of GH on insulin in the past
ten years because GH influences insulin sensitivity.
Recent research has shown that the hyperinsulinemia
leads to the change in both GH secretion and GH level
in both diabetes condition and non-diabetes condition.
This finding has a significant meaning for endocrine
diseases or hormone disorders, and the effect of insulin
on GH secretion and GH level should be emphasized .
GH is stimulated by endogenous GHRH, which is
controlled by hypothalamus and stimulates the GH
stored in pituitary to be released to the blood circulation.
And it is inhibited by SRIF or SS. Importantly, SS
could reduce the release of GH from GH-releasing cells
(somatotropes) in pituitary, preventing excessive GH.
So, GHRH and SS regulate GH secretion together to
keep the normal concentration of GH in circulation [9, 21, 22].
In summary, GH secretion depends on three decisive
factors: GHRH released by hypothalamus, SS in the
body especially in the hypothalamus, and the GH cells
which store GH in pituitary.
2.1 The effect of insulin on GH secretion and GH
level under diabetes or non-diabetes condition
In a healthy body, insulin and glucagon are main fac-
tors for regulating glucose concentration. GH’s effect
on blood glucose is similar to glucagon, which acceler-
ates gluconeogenesis and restrains the absorption of
glucose from circulation to cells, so there is a balance
between GH and insulin on regulating glycol-metabo-
lism. However, in patients with diabetes, insulin is
relatively or absolutely in deficiency. The balance
between GH and insulin is disturbed, and it not only
imposes inuences on blood glucose, but can cause a
series of impacts on GH secretion and level.
As it is mentioned, to analyse the effect of insulin on
GH secretion, three elements should be considered:
GHRH, SS, and somatotropes. In 1985, Shibasaki and
colleagues found that pretreatment of insulin could
weaken the GH response to the administration of
GHRH-44, which suggests that insulin may cause the
desensitization of GHRH receptors in GH secretion
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
cells and enhance the level of SS . Then in 1990,
scholars found the average GHRH levels were higher
in the control group than that of T1D subjects at all
stages after meals, while SS level had no difference .
Also, in T1D patients, the level of GH is higher, the
GHR level is lower than normal, and a raise in GH
secretion was observed following the reduction in insulin
level . All these data suggest that a higher level of
insulin brings down the sensitivity of GHRH receptors
in somatotropes, which restrains the hypothalamus-
stimulated GH secretion. Meanwhile, insulin in normal
physiological concentration maintains the level and
sensitivity of GHR and GHRH action on somatotropes,
promoting the normal release of GH from pituitary.
When the blood glucose concentration is inuenced
by some pathological conditions, SS participates in the
effect of insulin on GH. Insulin-induced hypoglycaemia
can stimulate GH secretion mainly through inhibiting
hypothalamic SS release . By contrast, when the
glucose concentration of blood is overloaded in diabetic
conditions, SS may be secreted in a greater level, and
reduce somatotrope-released GH. Insulin maintains the
balance with GH through SS. Even though one function
of SS is to restrict the glucagon, which is similar to
insulin, the overall effect of SS on glucose metabolism
does not completely accord with the level of insulin.
The further research on the interactive relationship
between the SS and insulin is needed.
In conclusion, insulin could maintain a balance with
GH in physiological conditions, which is essential for
glucose metabolism; but in diabetes, insulin may
reduce the sensitivity of GHRH receptor on somatotropes
and restrain GH secretion by increasing the level of SS.
GH could stay steady without changing with insulin’s
fluctuation because of self-regulation of GH. Insulin
regulates the secretion of SS and GH to better control
the blood glucose level. By realizing the relationship
among GH, insulin and their mediator SS, we may treat
diabetes from a new perspective, and better understand
how insulin-replacement therapy influences GH level
and secretion when treating diabetes. The mechanism
of insulin on GH may be different in T1D and T2D.
The matter about how the effect of insulin on GH
changes with different conditions of body and with
hormones’ concentrations need to be further studied. A
recent research in vitro has showed that somatotropes in
hypophysis possess many kinds of ion channels on their
membranes, especially Ca2+ channel, which is modied
by insulin, affects the signal transmission and then
exerts impact on the release of GH . This is a possible
regulation mechanism of insulin in a sub-cellular level.
2.2 The effect of insulin on GH secretion and GH
level under obese or non-obese condition
Obesity is a complex medical condition caused by the
combination of many factors, one of which is disorder
of lipid metabolism . Factors that can exert impacts
on lipogenesis or lipolysis lead to obesity. In mammal,
similar to glycometabolism, it is the balance between
GH and insulin that controls lipid metabolism. The
relationship between GH proles and obesity is proved
as enhanced obesity in patients lacking GH and in
animals, e.g. lit/lit mice, which cannot express GH .
Obesity is an important factor of decreased insulin
sensitivity and contributes to T2D. Therefore, obese
condition can influence both GH and insulin, and
influence the balance between them. The effect of
insulin on GH secretion and level under obese
condition also involves the effect of insulin on GHRH,
SS, and GH secreting cells.
De Schepper et al. found no overt relationship
between insulin and pulsatile GH secretion in both
obese and non-obese rats in an experiment of small
sample size, but the GH secretion was less and insulin
level was higher in obese group than that in non-obese
group . This suggested that there were other factors
participating in the balance between GH and insulin. In
2001, Wang et al. found that insulin level was higher in
obese children compared with that in non-obese
children, and GH levels were remarkably lower in
obese boys . When obesity occurs, the sensitivity of
insulin is lower, which brings hyperinsulinemia.
Increasing insulin stimulates SS secretion and inhibits
GH secretion. A study about children with obesity has
conrmed the idea that SS plays an essential role in the
connection between insulin and GH in obesity
condition. This study showed that, when chronic
increase appeared in SS secretion, pituitary-secreted
GH level would be reduced . Sauter et al. considered
that insulin rstly stimulated the release of catecholamines,
and then catecholamines took a second step action to
promote the increase in SS . In 2006, a study showed
that hypothalamus did not play an indispensable role in
regulating the secretion of GH. Unlike the regulation
pattern in diabetes mentioned above, the suppression of
GH in obesity condition is relatively independent of
GHRH and SS . Insulin resistance may exist in the
QIU Han et al.: Inuence of Insulin on GH Secretion, Level and Signaling 547
somatotropes, just like it exists in many other cells .
Insulin signal in somatotropes is a result of systemic
regulation, and suppresses GH release directly. Insulin
can complete this effect even in systemic insulin
resistance individuals such as T2D patients, suggesting
a relatively sensitive status of somatotropes to insulin
in obesity [70, 71]. It also leads to a new question: obesity
impairs the insulin signaling, so logically the effect of
insulin on somatotropes in pituitary should also be
attenuated . Why GH secretion and GH levels still be
suppressed by insulin-induced SS secretion? This
question is still open for further study. Gender is also a
crucial factor for the effect of insulin on GH. Androgen
may play an essential role in the difference .
Additionally, GH level in circulation is correlative
with the pulsatile secretion of GHRH, but it is not
absolutely depending on GHRH only. Cells expressing
GHR play a role in managing the GH levels. Insulin
treatment is found to enhance GH-induced JAK2 phos-
phorylation in accordance with the expression of
surface GHRs, but to decrease circulating GH, suggest-
ing that insulin may inuence GH level by inuencing
GHR sensitivity . Interaction of GH with other hor-
mones on a cellular of molecular level also inuences
GH level, including a variety of signal proteins and
many pathways, which will be discussed below. Most
signicantly, GH level tends to be closely related to the
insulin level in circulation. Chen et al. have veried a
reverse effect of dietary-induced weight gain on insulin
and GH levels in circulation by discussing which
comes rst, obesity or the decline of GH . Previous
studies tended to support the former. However, they
found the inhibition of pulsatile GH secretion coming
before dietary-induced weight gain (not obese yet), and
the level of GH, which showed the reverse relationship
with insulin, did not change parallelly with the circulat-
ing levels of NEFAs or glucose. Their result agreed
with Cornford’s study, which discovered that the
suppression of GH secretion and the improved insulin
sensitivity might be the reason for obesity, not the
result . The clinical application is that we may pre-
vent or cure obesity by monitoring and regulating the
balance between GH and insulin.
In summary, the regulation of GH secretion by
insulin in people with obesity is different with the way
in people suffering diabetes. IR plays an important role
in inhibiting GH secretion in obese condition, while SS
and other hormones may mainly account for insulin-
induced decline of GH secretion in diabetes. During the
diet-induced weight gain, the regulatory effect of
insulin on GH may be stronger than the effect of GH
on insulin. For maintaining the safe lower levels of
NEFA and blood glucose, insulin level will increase
and cause suppression of GH secretion and decline of
GH level after calorie intake .
2.3 Mechanisms behind the effect of insulin on GH
According to the discussion above, hypothalamus is an
important site for insulin to exert inuence on GH,
especially in diabetes, with the participation of GHRH,
SS and other hormones in the body, all of which lead to
inhibition of GH secretion and a lower GH level.
Hypothalamus is not the only target for GH level to be
influenced by insulin in obesity. The mediation of SS
secretion centrally and peripherally, the direct action of
insulin binding to IR, is very important for the regulation
of GH secretion and level. In addition, IGF plays an
important role. Recently IGF-1 has been considered an
inhibitor of GH secretion, and the GH/IGF-1 system
accounts for the visceral adiposity [9, 24]. This may be on
account of that IGF-1 and insulin have hybrid receptors .
Insulin can bind with the IGF receptor. If the level of
insulin is excessive, the prole of plasma IGF-1 will go
up, due to the lack of available receptor. IGF-1 gives
negative feedback to the GHRH/GH/IGF-1 axis, result-
ing in the decline of GH level. Meanwhile, the expres-
sion of GHRH and SS gene has no signicant change
in dietary-induced obesity . Somatotropes and IR
may be the targets for insulin to affect GH secretion
and level directly and indirectly. The body may
sacrifice normal weight in order to prevent normal
metabolism from hyperlipidemia. In other words, people
overeating and with hyperglycemia have to pay the
price -- the tendency to suffer obesity by restraining the
GH secretion and level in order to sustain the normal
lipid and glucose concentration. Also, according to
some in vitro studies, this mechanism should have
protected body from too much lipolysis, but it may easily
lose control due to the decline of the number of GHR
expressed in adipocytes in the obese [76, 77]. For the
regulation pattern of the whole process, see Fig. 2.
3 The post-GHR interaction between GH
and insulin: Influence of insulin on GH sig-
nalling and mechanism
The successful process of GH secretion and the mainte-
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
nance of GH level do not guarantee the successful per-
formance of GH. Insulin can exert effect on the post-
GHR process too. The insulin-induced impairment of
GH overall function may involve insulin’s inuence on
GH signalling inside cells. It is found that a physiologi-
cal dose of insulin is required for maintaining normal
liver GH signalling responsiveness both in vivo and in
vitro, and the lower fasting insulin was accompanied by
lower levels of GHR [6, 7, 78–80]. Crucial signal pathways
of GH have been already introduced above. Insulin has
different effect on these pathways, leading to the atten-
uation or enhancement of GH signalling. The interac-
tion between insulin and GH signalling is the basis for
understanding insulin’s effect on GH.
3.1 Shared signalling: the basis for the post-GHR
interaction between GH and insulin
Signalling of GH and insulin are not same in the receptor
level, but they partly begin to converge in the post-
GHR level. Decades ago, GH has shown the acute
insulin-like effect and chronic anti-insulin effect,
suggesting the shared signalling between the two hor-
mones [26, 81]. There are three main signal pathways as
mentioned above. GHR/JAK2/STATs and GHR/JAK2/
SHC/MAPK pathways mainly serve the function of
regulating the genes transcription for vital proteins
inside the nucleus, and GH/IRS/PI3K/Akt pathway
accounts for the regulation of lipometabolism and
glycometabolism. These pathways are shared between
GH and insulin for different purposes (see Fig. 3).
IR/IRS/PI3K/Akt is the vital pathway for insulin. It
has been found that this pathway participates most of
the cellular activities by insulin action such as glucose
transportation, glycogen synthesis, and suppression of
gluconeogenesis [82, 83]. Akt, a serine/threoine kinase, is
the most essential downstream molecule of PI3K. The
proteins in the downstream of Akt includes glycogen
synthase kinase-3 (GSK-3), BAD, forkhead box O1
(FoxO1) transcription factor. These effectors of Akt
have different destination, directly or indirectly affect-
ing the function of insulin signalling. Noticeably, GH
regulates metabolism of lipid and glucose through
PI3K/Akt pathway [82, 83], so insulin can interact or
cause crosstalk with GH in this pathway, through
Akt [84–86]. Moreover, PI3K is indispensable for the acti-
Fig. 2. The regulation pattern of GH proles in obesity. GH and insulin levels maintain a balance in body. They jointly control fat me-
tabolism and glucose metabolism. Overtaking calories leads to a high level of glucose and lipid in circulation, which will stimulate the
secretion of insulin and somatostatin. Also, a high level of blood lipid will tend to inhibit GH secretion. As insulin and somatostatin
increases, GH secretion decreases, so does its level in circulation. Moreover, GHR level decreases with its sensitivity being attenuated,
leading to the dysfunction of GHR and noneffective GH signaling. As a result of these actions, lipolysis is accelerated and lipogenesis
is restrained. In this condition, the concentrations of lipid and glucose can be controlled, although the weight gain increases. Abbrevia-
tions: GH, growth hormone; GHR, growth hormone receptor.
QIU Han et al.: Inuence of Insulin on GH Secretion, Level and Signaling 549
vation of MAPK [57, 87]. The signicance of PI3K/Akt to
both GH and insulin signalling is obvious.
MAPK pathway is also shared by GH and insulin. As
mitogen-activated protein kinase, MAPK plays a role
in promoting the growth, and has a minor role in
regulating the metabolism. PI3K and Ras-Raf-Mek-Erk
pathway are indispensable in stimulating the MAPK [83, 88].
Interestingly, MAPK has been shown to weaken the
signal of regulating metabolism emanated by insulin .
Fig. 3. Shared signal pathways between insulin and GH. GH signaling involves three signal pathways. The rst one mediated by
STATs proteins, which can activate SOCSs proteins, is shared by insulin with the particular participation of STAT5B. Insulin activates
SOCSs, which will block the combination of JAK2 and GHR. Also, SOCSs can attenuate the interaction between GHR and IRS. The
second way shared by insulin is mediated by SHC, a cytosolic protein. The engagement of SHC is responsible for the activation of
MAPK cascades. Insulin can enhance the tyrosine phosphorylation of IRS-1, which can facilitate MAPK activation. Insulin shows
an additive effect on GH-stimulated MAPK activation, by facilitating the activation of IRS. Another signal pathway of GH shared
by insulin is PI3K/Akt pathway. Tyrosine phosphorylation of IRS-1 and -2 leads to the activation of PI3K, a SH2 domain containing
protein, and its downstream Akt cascade. The activation of PI3K/Akt pathway is essential for the activation of other pathways, and
insulin coordinates GH’s insulin-like metabolic regulation in this pathway. Pathways mediated by STATs and MAPK are two major
pathways for the regulation of gene transcription, including genes of growth, metabolism and differentiation; PI3K/Akt pathway is
involved in activation of cytoplasmic targets and is important for metabolic regulation of GH and insulin, especially the regulation on
glucose and lipid in circulation. The shared signaling is the basis of the effect of insulin on GH signaling. Abbreviations: −, inhibition;
P, phosphotyrosine; GH, growth hormone; GHR, growth hormone receptor; INS, insulin; STAT, signal transducers and activators of
transcription; IRS, insulin receptor substrate; SOCSs, suppressors of cytokine signaling; SHC, src homology and collagen proteins;
MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B.
Since GH and insulin have reverse effect on the regula-
tion of glucose and lipid metabolism, MAPK may get
involved in the crosstalk between GH and insulin.
STAT pathway is a necessary pathway for GH to
regulate gene transcription for vital proteins, and it has
been elucidated that STAT5 is sensitive to pulsatile
secretion of GH . According to Chen’s study in vitro,
STAT5b-Ct is phosphorylated by IR kinase domain
which was depurated. In the cells which overexpress
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
IR, STAT5b-Ct phosphorylation and overexpressed
endogenetic STAT5 were found . Also, evidence
showed that SOCSs mRNA expression controlled by
insulin is also mediated by STAT5 . Insulin interacts
with many other hormones including GH, luteinizing
hormone (LH), leptin and prolactin (PRL) in a
STAT5-dependent way [29, 92–94]. JAK2 may play a part
in the phosphorylation of STAT5 . However, Zovnic
et al. found that insulin could not stimulate the
phosphorylation of STAT5 in vitro, instead, GH could.
This study was veried in vivo . Whether STAT5 can
be activated by the insulin depends on the types of cells
and tissues and the physiological condition. Nowadays,
most scholars support that STAT5 is a physiological
substrate of IR . Therefore, interaction can be medi-
ated by STAT5, which is important downstream protein
for both insulin and GH signalling.
3.2 The effect of insulin on MAPK pathway of GH
An in vitro study found that GH and insulin both can
stimulate the maximum activation of MAPK pathway
in a time- and dose- dependent way . Insulin co-treatment
with different concentrations of GH showed an additive
effect on GH-stimulated MAPK activation when GH
concentration was low (5 and 25 ng/mL). Insulin
pretreatment (200 nmol/L insulin was added to GH 20
min in advance) had no effect on GH-induced MAPK
activation . However, in vivo study showed that insulin
did not enhance GH-induced MAPK, suggesting
that insulin might play a positive role in GH-induced
MAPK signalling when the concentration ratio of GH
to insulin was suitable. It is also considered that IRS-1
can facilitate GH-induced MAPK activation. In the
same study, the co-treatment of insulin and GH
enhanced the tyrosine phosphorylation of IRS-1, and
the GH-induced MAPK activation also rose. We consider
that pretreatment of insulin-induced IRS may have
already been recruited before the treatment of GH, so
no additive effect was observed.
Mek/Erk can be phosphorylated without the involve-
ment of JAK2, Ras, and Raf-1, instead, with the
enhanced cell membrane translocation of Mek1/2.
These ndings suggest that insulin is indispensable for
GH-induced Erk1/2 activation and provide us a possible
explanation for the mechanism of insulin’s additive
effect on GH-induced MAPK signalling . For the
effect of insulin on the GH/MAPK pathway, the role of
insulin may be not only additive, but also irreplaceable
for sensitivity of membrane kinase.
3.3 The effect of insulin on JAK2/STAT5 pathway
of GH signalling
In 1999, Ji  found insulin impairs GH signalling by
affecting JAK2/STAT5 pathway in vitro. Continuous
high concentration insulin treatment inhibited GH binding
and the GHR level, as well as the phosphorylation of
JAK2 and STAT5B in a time-dependent way .
However, some studies showed that high levels of insulin
and insulin treatment can enhance GH-induced JAK2
phosphorylation in accordance with expression of
surface GHRs . Zhang et al. found that insulin per se
cannot induce STAT5 activation, conicting with previous
studies [12, 36, 90, 96]; however, insulin did improve GH-
induced STAT5 tyrosine phosphorylation in 3T3-F442A
adipocytes, both time- and dose-dependently. This
result is consistent with the study from Xu et al. .
This additive-effect was more overt when given
pre-treatment of insulin, and conclusions were con-
rmed in vivo . These experiments suggest that insu-
lin’s inuence on GH/GHR/JAK2/STAT5 is not mono-
directional or monotypical, but depends on conditions.
Normal concentration of insulin is a necessity of the
responsive of GH signalling by maintaining the level of
GHR and phosphorylation of proteins in JAK2/STAT5
pathway. However, insulin above suitable range causes
inhibition of GH signal transmission. In the future, we
need to nd the relationships between effect, time and
dose of insulin treatment, pre-treatment, or the co-treat-
ment with GH. Also, the applicability in the counterpart
of human still need to conrm [13, 74, 97]. A curve graph
which shows how GH signalling intensity changes with
time and dose of insulin treatment, as well as other
factors should be made. Related endocrine diseases can
be better understood, and more evidence can be provided
for clinical therapeutics.
3.4 The effect of insulin on PI3K/Akt pathway of
PI3K is the most important downstream binding protein
for IRS. The IRS/PI3K/Akt pathway is essential for
insulin to implement metabolic regulation function and
for activation of MAPK [57, 87]. There has been substantial
evidence suggesting that PI3K/Akt mediates crosstalk
between GH and insulin signalling [84, 86]. A research
showed that under sepsis, there was a GH-resistant
condition, but when the sepsis objects were treated with
insulin, GHR and IGF-1 were back to normal levels,
and GH-resistance was alleviated. It was also found
QIU Han et al.: Inuence of Insulin on GH Secretion, Level and Signaling 551
that when PI3K/Akt pathway was blocked, the allevia-
tion effect of insulin could not work anymore. This
research suggested that in the pathology condition, a
suitable range of insulin can help GH maintain normal
function in the cellular level by regulating the IRS/
PI3K/Akt pathway . For GH, PI3K/Akt pathway is
used for metabolic regulation in an insulin-like way
and it plays a coordinate role with insulin. Therefore,
another effect of insulin on PI3K/Akt pathway mainly
refers to coordinating GH’s insulin-like metabolic
regulation, including accelerating the transportation of
blood glucose and amino acid into cells, down-regulating
the blood glucose level, and inhibiting the lipolysis. As
to the long-term effect of GH, namely, anti-insulin
effect, it may involve insulin’s effect on other pathways
of GH’s signalling.
3.5 Mechanisms of the effect on GH signalling by
In combination with previous experiment data, if insulin
is pretreated on GH system, inslin is more likely to
exert suppressive impact on the GH signalling when
the period of insulin pretreatment is relatively long.
This mechanism may involve SOCSs. Short period (less
than 1 h) of pretreatment can help GHR maintain higher
abundance, but with the time span increasing, the insulin
will activate the STAT/SOCS pathway. SOCSs are able
to restrain JAK2 activity, so long period of insulin
pretreatment can interfere with the GH-induced phos-
phorylation of downstream protein .
For the co-treatment, time and dose are important
factors. According to Zhang’s study , it is hypothe-
sized that the dose of GH is more decisive than the
dose of insulin. When insulin’s dose did not change, the
change of GH dose could sharply affect the intensity of
signal molecules’ phosphorylation; however, when the
dose of GH was xed, even the dose of insulin changed
in ten-fold level, it only had a little effect on the result.
Both GH and insulin has the ability to activate down-
stream proteins, but the ability of GH may prevail with-
in a certain range. Therefore, once GH takes control the
path, insulin cannot compete. This hypothesis also
explained why the pretreatment of insulin is more
effective than co-treatment of GH and insulin: pretreat-
ment of insulin can help itself to take prior control of
the pathway, which can offset its weaker ability.
Considering all the work done, there are other factors
that affect insulin’s inuence on GH signalling. Besides
time and dose of insulin’s and GH treatment (including
the ratio of dose and time), possible factors include the
schedule and order when adding reagents, the whole
circumstance and condition of experiment, types of cell
and tissue and creatures used, all of which should be
taken into consideration. Just as it is mentioned, there
are many hormones interacting with GH or insulin via
their shared signalling. The reason why in vivo study is
different from in vitro study is that in vivo study tends
to be affected by a mixed regulation from other hor-
mones, such as leptin and ghrelin [92, 99, 100]. GHR should
also be taken into consideration. In 2004, Rhoads et al.
found that insulin enhanced the richness of the GHR
both in liver and adipose tissue of peri-parturient dairy
cows without affecting JAK2 and STAT5 proteins. It
implied that insulin can exert impact on GH signalling
through GHR . Excess insulin can impair the sensi-
tivity of GHR, while suitable range of insulin maintains
normal GHR level. GHR, IR and IGF-IR are concomi-
tant in the lipid raft, which offers a site for these mole-
cules to interact with each other, and this microcosmic
reciprocity may be the cornerstone of crosstalk between
signal pathways [101–103].
Increasing evidence implies that insulin can exert ac-
tions on every part when GH is performing its function.
A physiological dose of insulin is necessary for the
maintenance of the level and sensitivity of GHR and
the action of GHRH on somatotropes, while excessive
insulin restrains the hypothalamus-stimulated secretion
of GH by attenuating the sensitivity of GHRH recep-
tors on GH secretion cells. Insulin also exerts effect on
GH secretion by inuencing the level of blood glucose
concentration and SS, especially in diabetes. Insulin’s
action on GH level is related to GH secretion and GHR
sensitivity, as well as the condition of the body espe-
cially the obesity. Bodies with excess calories con-
sumption have a reverse relationship between GH and
insulin. Insulin implements this effect by regulating
lipolysis and lipogenesis. IGF also get involved in the
insulin’s effect on pre-receptor process of GH. In
future, we may explore other possible regulation
pattern or related factors besides hypothalamus and IR,
and nd out how insulin works on them.
GH signalling is also affected by insulin because they
share signal pathways in the post-GHR signalling.
Insulin affects GH signalling in a time- and dose-
dependent way, and multiple factors are involved in
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
this process, including IRSs, SOCSs and the sensitivity
of GHR. Insulin can activate IRS, which facilitates
GH-induced MAPK pathway. Insulin also stimulates
the phosphorylation of STAT5, and then SOCSs, which
can restrain the function of JAK2 and GHR/STAT5
pathway, but the reason of a few conflicting results
from in vivo and in vitro studies needs further research.
Insulin helps GH maintain normal function by regulating
the IRS/PI3K/Akt pathway in the cellular level in the
pathological condition. This process may involve other
In future, we should focus on the details of factors
and genes responsible for the interaction between insulin
and GH in different conditions. More substantial
evidence is in need for diagnosis and therapies of
endocrine disorders in clinical medicine eld.
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